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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first-line drugs for advanced non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. However, the development of TKI resistance is a major clinical challenge. Here we show that the adipophilin/adipose differentiation-related protein perilipin (PLIN)2 was upregulated in gefitinib-resistant PC9R cells; PLIN2 knockdown in PC9R cells conferred gefitinib resistance by inhibiting cancer cell apoptosis in vitro and in vivo and by inducing mitochondrial dysfunction and caspase activation. PLIN2 was also shown to activate EGFR/AKT/survivin signalling and was overexpressed in gefitinib-resistant cells in clinical samples. These results indicate that PLIN2 confers gefitinib resistance in lung cancer by inhibiting apoptosis and activating the EGFR/AKT/survivin pathway, and is thus a potential therapeutic target in EGFR TKI-resistant NSCLC patients. www.impactjournals.com/oncotarget/ Oncotarget, Advance Publications 2018

PLIN2 confers gefitinib resistance by inhibiting cell apoptosis via activation of EGFR/AKT/survivin in PC9R cells